Tay-Sachs disease is an inherited disorder caused by mutation in the alpha-chain of beta-hexosaminidase A, a lysosomal enzyme composed of two polypeptides designated the alpha and beta chains. The disease is heterogeneous displaying a wide range of severity and age of onset. An early onset and fatal form of the disorder referred to as "classic" Tay-Sachs disease has a ten fold higher gene frequency among the Ashkenazi Jews and a population of non-Jewish French Canadians located in Eastern Quebec. We previously isolated and characterized a cDNA clone containing the entire coding sequence for the alpha-chain of beta-hexosaminidase. During the past year we have utilized this clone to study the genetic lesions present in the alpha-chain gene of Tay-Sachs patients of Ashkenazi Jewish and non-Jewish French Canadian origin. We have found that the mutation differs in these two groups. The alpha-chain gene of the Ashkenazi Jewish patient appears intact suggesting a subtle genetic lesion. In contrast, the alpha-chain gene of the non-Jewish French Canadian patients has a 5' deletion of approximately 7.4 kilobases.